TY - JOUR
T1 - Modelling of a nanotherapeutic "stroma" to deliver LIF, or XAV939, for promotion of human fetal dopaminergic cells in treatment of Parkinson's disease
JF - Disease Models &amp; Mechanisms
JO - Dis Models Mech
M3 - 10.1242/dmm.015859
AU - Zhao, Jing-Wei
AU - Dyson, Sean C.
AU - Kriegel, C.
AU - Tyers, Pam
AU - He, Xiaoling
AU - Fahmy, Tarek M.
AU - Metcalfe, Su M.
AU - Barker, Roger A.
Y1 - 2014/01/01
UR - http://dmm.biologists.org/content/early/2014/07/25/dmm.015859.abstract
N2 - The endogenous reparative capacity of the adult human brain is low and chronic neurodegenerative disorders of the central nervous system represent one of the greatest areas of unmet clinical need in the developing world. Novel therapeutic strategies to treat them include (i) growth factor delivery to boost endogenous repair and (ii) replacement cell therapy, including dopaminergic neurons for Parkinson's Disease (PD). However these approaches are limited not only by rapid degradation of growth factors, but also by the poor availability and survival of implanted cells that lack the necessary stromal support. We therefore hypothesised that provision of a transient artificial stroma for paracrine delivery of pro-survival factors may overcome both of these issues. Using leukaemia inhibitory factor (LIF) - a proneural, reparative cytokine - formulated as target-specific PLGA nano-particles (LIF-nano) - we discovered that attachment of LIF-nano to freshly isolated fetal dopaminergic cells improved their survival fourfold: furthermore, in vivo, the numbers of surviving human fetal dopaminergic cells tended to be higher at 3 months after grafting into the striatum of nude rats. In addition we also analysed the effect of a novel nano-stroma incorporating XAV939, a potent inhibitor of the developmentally important wnt/β-catenin signalling pathway, to investigate whether it could also promote the survival and differentiation of human fetal dopaminergic precursors and found both TH+ neurons and total neurons were increased in number. This is the first demonstration that LIF-nano-stroma, and XAV-nano-stroma, each have pro-survival effects on human dopaminergic neurons, with potential value for target-specific modulation of neurogenic fate in cell based therapies for PD.
ER -